Mitogen-activated protein (MAP) kinase signaling through calcineurin-dependent pathways in cardiac fibroblasts

ABSTRACT Malignant melanoma, an aggressive and increasingly common cancer, is characterized by a strikingly high rate (70%) of mutations in BRAF, a key component of the mitogen-activated protein (MAP) kinase signaling pathway. How signaling events downstream from BRAF affect the underlying program of gene expression is poorly understood. We show that the Brn-2 POU domain transcription factor is highly expressed in melanoma cell lines but not in melanocytes or melanoblasts and that overexpression of Brn-2 in melanocytes results in increased proliferation. Expression of Brn-2 is strongly upregulated by Ras and MAP kinase signaling. Importantly, the Brn-2 promoter is stimulated by kinase-activating BRAF mutants and endogenous Brn-2 expression is inhibited by RNA interference-mediated downregulation of BRAF. Moreover, silent interfering RNA-mediated depletion of Brn-2 in melanoma cells expressing activated BRAF leads to decreased proliferation. The results suggest that the high levels of Brn-2 expression observed in melanomas link BRAF signaling to increased proliferation.

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Mitogen-activated protein kinase activation and regulation in the pressure-loaded fetal ovine heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00984.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. H1587-H1595 ◽

Cited By ~ 11

Author(s):

Aaron K. Olson ◽

Kristin N. Protheroe ◽

Jeffrey L. Segar ◽

Thomas D. Scholz

Keyword(s):

Map Kinase ◽

Signaling Pathways ◽

Fetal Heart ◽

Left Ventricular ◽

Heart Weight ◽

Kinase Signaling ◽

Protein Levels ◽

Pressure Load ◽

Map Kinase Signaling ◽

Mitogen Activated Protein

The mitogen-activated protein (MAP) kinase signaling pathways help to mediate the hypertrophic response of the pressure-loaded adult heart, although their importance in fetal myocardium is less known. The goal of this study was to determine the role the MAP kinase signaling pathways play in regulating the response of the fetal heart to a pressure load. Aortic (Ao) and pulmonary artery (PA) bands were placed in 132-day fetal sheep for 7 days. Protein levels of the total and active (phosphorylated) terminal MAP kinases extracellular signal-regulated kinase (ERK/P-ERK), c-Jun NH2-terminal kinase (JNK/P-JNK), and p38/P-p38 and the MAP kinase phosphatases MKP-1, MKP-2, and MKP-3 were made in the right and left ventricular (RV and LV) free walls. In both Ao- and PA-banded animals, total heart weight normalized to body weight was significantly increased, largely due to an increase in RV free wall mass in the Ao-banded animals and an increase in septal mass in the PA-banded fetuses. Total protein levels of the three terminal kinases and of P-ERK and P-JNK remained stable in both groups of banded animals. However, P-p38 was significantly increased in RV and LV of Ao- and PA-banded fetuses. Whereas MKP-1 and MKP-2 protein levels were unchanged following Ao- and PA-banding, MKP-3 protein levels were significantly increased in the RV of the PA-banded animals. These findings indicate that the MAP kinase signaling pathways are active in the fetal heart and help to modulate the response of prenatal myocardium to a pressure load.

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Phosphorylation of the Kinase Interaction Motif in Mitogen-activated Protein (MAP) Kinase Phosphatase-4 Mediates Cross-talk between Protein Kinase A and MAP Kinase Signaling Pathways

Journal of Biological Chemistry ◽

10.1074/jbc.m111.255844 ◽

2011 ◽

Vol 286 (44) ◽

pp. 38018-38026 ◽

Cited By ~ 14

Author(s):

Robin J. Dickinson ◽

Laurent Delavaine ◽

Rocío Cejudo-Marín ◽

Graeme Stewart ◽

Christopher J. Staples ◽

...

Keyword(s):

Protein Kinase ◽

Map Kinase ◽

Protein Kinase A ◽

Signaling Pathways ◽

Cross Talk ◽

Kinase Signaling ◽

Map Kinase Phosphatase ◽

Protein Map ◽

Mitogen Activated Protein ◽

Kinase A

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Distinct Roles for Two Gα–Gβ Interfaces in Cell Polarity Control by a Yeast Heterotrimeric G Protein

Molecular Biology of the Cell ◽

10.1091/mbc.e07-04-0385 ◽

2008 ◽

Vol 19 (1) ◽

pp. 181-197 ◽

Cited By ~ 22

Author(s):

Shelly C. Strickfaden ◽

Peter M. Pryciak

Keyword(s):

Map Kinase ◽

G Protein ◽

De Novo ◽

Cell Polarization ◽

Kinase Signaling ◽

Directional Growth ◽

Heterotrimeric G Protein ◽

Map Kinase Signaling ◽

Mitogen Activated Protein ◽

Cell Asymmetry

Saccharomyces cerevisiae mating pheromones trigger dissociation of a heterotrimeric G protein (Gαβγ) into Gα-guanosine triphosphate (GTP) and Gβγ. The Gβγ dimer regulates both mitogen-activated protein (MAP) kinase cascade signaling and cell polarization. Here, by independently activating the MAP kinase pathway, we studied the polarity role of Gβγ in isolation from its signaling role. MAP kinase signaling alone could induce cell asymmetry but not directional growth. Surprisingly, active Gβγ, either alone or with Gα-GTP, could not organize a persistent polarization axis. Instead, following pheromone gradients (chemotropism) or directional growth without pheromone gradients (de novo polarization) required an intact receptor–Gαβγ module and GTP hydrolysis by Gα. Our results indicate that chemoattractant-induced cell polarization requires continuous receptor–Gαβγ communication but not modulation of MAP kinase signaling. To explore regulation of Gβγ by Gα, we mutated Gβ residues in two structurally distinct Gα–Gβ binding interfaces. Polarity control was disrupted only by mutations in the N-terminal interface, and not the Switch interface. Incorporation of these mutations into a Gβ–Gα fusion protein, which enforces subunit proximity, revealed that Switch interface dissociation regulates signaling, whereas the N-terminal interface may govern receptor–Gαβγ coupling. These findings raise the possibility that the Gαβγ heterotrimer can function in a partially dissociated state, tethered by the N-terminal interface.

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Proteolytic Inhibition of Salmonella enterica Serovar Typhimurium-Induced Activation of the Mitogen-Activated Protein Kinases ERK and JNK in Cultured Human Intestinal Cells

Infection and Immunity ◽

10.1128/iai.70.1.86-95.2002 ◽

2002 ◽

Vol 70 (1) ◽

pp. 86-95 ◽

Cited By ~ 30

Author(s):

Tracey L. Mynott ◽

Ben Crossett ◽

S. Radhika Prathalingam

Keyword(s):

Map Kinase ◽

Signaling Pathways ◽

Salmonella Enterica ◽

Map Kinases ◽

Inflammatory Responses ◽

Cysteine Proteases ◽

Kinase Signaling ◽

Map Kinase Signaling ◽

Serovar Typhimurium ◽

Mitogen Activated Protein

ABSTRACT Bromelain, a mixture of cysteine proteases from pineapple stems, blocks signaling by the mitogen-activated protein (MAP) kinases extracellular regulated kinase 1 (ERK-1) and ERK-2, inhibits inflammation, and protects against enterotoxigenic Escherichia coli infection. In this study, we examined the effect of bromelain on Salmonella enterica serovar Typhimurium infection, since an important feature of its pathogenesis is its ability to induce activation of ERK-1 and ERK-2, which leads to internalization of bacteria and induction of inflammatory responses. Our results show that bromelain dose dependently blocks serovar Typhimurium-induced ERK-1, ERK-2, and c-Jun NH2-terminal kinase (JNK) activation in Caco-2 cells. Bromelain also blocked signaling induced by carbachol and anisomycin, pharmacological MAP kinase agonists. Despite bromelain inhibition of serovar Typhimurium-induced MAP kinase signaling, it did not prevent subsequent invasion of the Caco-2 cells by serovar Typhimurium or alter serovar Typhimurium -induced decreases in resistance across Caco-2 monolayers. Surprisingly, bromelain also did not block serovar Typhimurium-induced interleukin-8 (IL-8) secretion but synergized with serovar Typhimurium to enhance IL-8 production. We also found that serovar Typhimurium does not induce ERK phosphorylation in Caco-2 cells in the absence of serum but that serovar Typhimurium-induced invasion and decreases in monolayer resistance are unaffected. Collectively, these data indicate that serovar Typhimurium-induced invasion of Caco-2 cells, changes in the resistance of epithelial cell monolayers, and IL-8 production can occur independently of the ERK and JNK signaling pathways. Data also confirm that bromelain is a novel inhibitor of MAP kinase signaling pathways and suggest a novel role for proteases as inhibitors of signal transduction pathways in intestinal epithelial cells.

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